Formulation and evaluation of dextromethorphan hydrobromide sustained release tablets

Sustained release (SR) matrix tablets of dextromethorphan hydrobromide were prepared by wet granulation using hydroxypropyl methyl cellulose (HPMC-K-100 CR) as the hydrophilic rate controlling polymer. The effect of the concentration of the polymer and different fillers on the in vitro drug release rate was studied. The studies indicated that the drug release can be modulated by varying the concentration of the polymer and the fillers. A complete cross-over bioavailability study of the optimized formulation of the developed sustained tablets and marketed immediate release tablets was performed on six healthy male volunteers. The extent of absorption of drug from the SR tablets was significantly higher than that for the marketed dextromethorphan hydrobromide tablet because of lower elimination rate and longer half-life.     

Influence of Carbopol 71G-NF on the release of dextromethorphan hydrobromide from extended-release matrix tablets

The objective of this study was to evaluate the potential of Carbopol^® 71G-NF on the release of dextromethorphan hydrobromide (DM) from matrix tablets in comparison with hydroxypropyl methylcellulose (HPMC^® K15M) and Eudragit^® L100-55 polymers. Controlled release DM matrix tablets were prepared using Carbopol 71G-NF, HPMC K15M, and Eudragit L100-55 at different drug to polymer ratios by direct compression technique. The mechanical properties of the tablets as tested by crushing strength and friability tests were improved as the concentration of Carbopol, HPMC, and Eudragit increased. However, Carbopol-based tablets showed a significantly (P?<?0.05) higher crushing strength and a lower friability than HPMC and Eudragit tablets. No significant differences in weight uniformity and thickness values were observed between the different formulations. It was also found that Carbopol significantly (P?<?0.05) delayed the release of DM in comparison with HPMC K15M and Eudragit L100-55. A combination of HPMC K15M and Eudragit L100-55 in a 1:1 ratio at 20 and 30% significantly (P?<?0.05) delayed the release of DM than Eudragit L100-55 alone. Moreover, blends of Carbopol and HPMC at a 1:1 ratio at the 10, 20, and 30% total polymer concentration were investigated. The blend of Carbopol and HPMC at 10% level significantly (P?<?0.05) slowed the release of DM than Carbopol or HPMC alone, whereas blends at 20 and 30% level significantly (P?<?0.05) delayed the release of DM compared with HPMC or Carbopol alone. The results with these polymer blends showed that it was possible to reduce the total amount of polymers when used as a combination in formulation.     

氢溴酸右美沙芬缓释片的制备及释放度研究

研究氢溴酸右美沙芬（DMB）凝胶骨架缓释片的制备和体外释放特性。方法：以羟丙基甲基纤维素（HPM）、已基纤维素（EC）和乳糖（Lactose）为辅料,采用均匀设计方法优化处方研制成氢溴酸右美沙芬凝胶骨架片,并研究了制片压力、释药介质的pH值、稀释剂的性质、辅料的粘度和用量等因素对DMB缓释片释药特性的影响。结果：经处方优化研制出的DMB缓释片8h体外释药90％左右,其释药曲线符合Miguchi动力学模型,不同时间的释放参数分别为t0．5＝2．8h,t0．9＝8．02h。结论：氢溴酸右美沙芬适合制成凝胶骨架缓释片,其释药速率随稀释刑或阻滞剂的用量而改变。     

氢溴酸加兰他敏贴剂的制备及体外释放和透皮特性研究

目的：制备氢溴酸加兰他敏贴剂,并对其体外释放度和体外透皮特性进行考察。方法：采用丙烯酸酯乳液型压敏胶为基质制备氢溴酸加兰他敏贴剂,按《中华人民共和国药典》规定方法进行贴剂的体外释放度测定;采用改良Franz扩散池,以离体小鼠皮肤为屏障进行氢溴酸加兰他敏贴剂的体外透皮特性研究。结果：氢溴酸加兰他敏贴剂的体外释放符合Higu-chi方程,24 h累积释药量占总药量的41.81%;体外透皮符合零级方程,24 h累积渗透量占总药量的19.99%。结论：采用丙烯酸酯乳液型压敏胶为基质制备的氢溴酸加兰他敏贴剂具有较好的体外释放和透皮特性。     

氢溴酸加兰他敏口服液及片剂的人体生物等效性研究

目的:采用HPLC-RF检测法测定氢溴酸加兰他敏的血药浓度,研究其在人体内的药动学和生物等效性。方法:24例健康男性志愿者单剂量随机交叉口服5 mg加兰他敏口服液(受试制剂)和片剂(参比制剂)。血浆样品经碱化后用乙醚提取,采用反相HPLC-RF法测定血浆中加兰他敏浓度,检测波长:激发波长290 nm,发射波长320 nm。采用3P97药动学软件计算药动学参数和相对生物利用度,并对参数进行方差分析和双单侧t检验。结果:加兰他敏口服液和片剂的主要药动学参数:Cmax分别为(31．53±5．59)和(33．44±5．72)μg·L-1;Tmax分别为(1．66±0．79)和(1．51±0．72)h;t1/2分别为(7．06±2．16)和(6．64±2．30)h;AUC0～∞分别为(340．6±77．2)和(325．5±77．7)μg·h·L-1。氢溴酸加兰他敏口服液相对生物利用度为105．6％。结论:加兰他敏口服液和片剂生物等效。     

Estimation of the percolation thresholds in dextromethorphan hydrobromide matrices

Percolation theory is a multidisciplinary theory that studies chaotic systems. It has been applied in the pharmaceutical field since 1987. Knowledge of the percolation threshold — one of the most important concepts in percolation theory — results in a clear improvement of the solid dosage form design. The percolation threshold is the concentration showing the maximum probability to obtain, for the first time, a percolating cluster of a substance. In this work, the percolation thresholds of dextromethorphan·HBr/Eudragit^® RS-PM inert matrices were estimated. The drug percolation threshold was estimated as 0.3691±0.0541 (P=0.05) of the total porosity (ranging between 23 and 36% w/w of drug). The SEM micrographs of the matrices are consistent with the estimated percolation range. In agreement with previous reports, different percolation thresholds were found for the matrix forming excipient Eudragit^® RS-PM. The site percolation threshold (based on the release properties) ranged between 10 and 20% v/v of the excipient, the site-bond percolation threshold (estimated from the mechanical properties) between 29.5 and 34% v/v of the excipient and the swelling percolation threshold between 34.3 and 46.9% v/v of the excipient. These percolation ranges are in agreement with those found previously for Eudragit^® RS-PM matrices containing naltrexone·HCl and morphine·HCl.     

氢溴酸右美沙芬片健康人体生物等效性

目的 :研究氢溴酸右美沙芬片在健康人体的药动学及相对生物利用度。方法 :8名健康受试者单剂量随机交叉口服氢溴酸右美沙芬片参比制剂和被试制剂 6 0mg ,采用HPLC法测定用药后不同时间的血药浓度。结果 :2种制剂的体内过程均符合一房室开放模型 ,参比制剂和被试制剂的tmax分别为 (2 72± 0 2 1)h和 (2 74± 0 19)h ,cmax分别为 (5 5 1± 0 4 4) μg·L-1和(5 5 8± 0 2 7) μg·L-1,AUC分别为 (4 5 3± 2 9) μg·h·L-1和 (4 5 7± 3 0 ) μg·h·L-1,被试制剂的相对生物利用度为 (10 1±5 9) %。结论 :2种制剂具有生物等效性。     

对乙酰氨基酚、氢溴酸右美沙芬在口服液中的原辅料相容性研究

目的 制备以对乙酰氨基酚（PA）和氢溴酸右美沙芬（DX）为主成分的复方对乙酰氨基酚口服液,考察PA、DX与辅料间的相容性。方法 建立适合口服液中PA、DX含量测定和有关物质检查的高效液相色谱（HPLC）法,将PA和DX分别与辅料（甘油、丙二醇、山梨醇、三氯蔗糖、苯甲酸钠、依地酸二钠、黄原胶、色素、香精）按一定比例混合、加水溶解并调节pH值,制备二元相容性样品,并取制剂、PA阴性制剂、DX阴性制剂,于高温（60℃）和光照（4 500 lx）条件下破坏0、5、10 d,记录溶液性状、pH值;采用HPLC法检测主成分和有关物质含量变化。结果 建立的HPLC法专属性好,线性关系良好（r＞0.999）,回收率、精密度和耐用性等均符合要求。在光照条件下,除棕色PET瓶包装复方对乙酰氨基酚口服液外,相容性样品从木槿紫色变为深蓝色。与0 d相比,样品pH值逐渐增大,高温条件下增加幅度整体高于光照条件;PA阴性制剂、DX阴性制剂和复方对乙酰氨基酚口服液,作为一个比较完整的制剂体系,pH值变化不明显。光照条件下PA和DX的相容性样品含量降低程度总体高于高温条件;PA与依地酸二钠、黄原胶和香精的相容性样品含量降低幅度高于PA溶液;DX与苯甲酸钠和依地酸二钠的辅料相容性样品含量降低幅度较高;辅料相容性样品含量降低幅度均在2.5%以下。PA总杂质最高达到1.3%,DX总杂质最高达到2.25%,DX在高温条件下稳定性较高,在光照条件下稳定性较差。结论 光照和pH值对主成分稳定性影响较大,将主成分制备成具有一定pH值缓冲区间的制剂,并采用避光性较好的包装材料能够有效提高PA和DX的稳定性。     

Influence of methacrylic and acrylic acid polymers on the release performance of weakly basic drugs from sustained release hydrophilic matrices

Weakly basic drugs and their salts exhibit a drop in aqueous solubility at high pH conditions, which can result in low and incomplete release of these drugs from sustained release formulations. The objective of this study is to modulate matrix microenvironmental pH by incorporation of acidic polymers and thus enhance the local solubility and release of basic drugs in high pH environment. Two weakly basic drugs, papaverine hydrochloride and verapamil hydrochloride with widely different pKa and aqueous solubilities at the pH of interest (6.8), were investigated for their release from hydrophilic matrices and the effect of a methacrylic (Eudragit L100-55) and an acrylic acid polymer (Carbopol 71G), were studied. For papaverine HCl, release increased with an increase in the levels of the acidic polymer used. Direct measurement of matrix pH using microelectrodes illustrated that the mechanism of release enhancement was based on modulation of microenvironmental pH. For verapamil HCl, incorporation of L100-55 resulted in release retardation due to an interaction between the anionic polymer and the cationic drug and the extent of retardation increased with an increase in the polymer level. The interaction product was characterized by NIR, FT-IR, and MTDSC techniques. Verapamil HCl release from Carbopol 71G based matrix tablets was higher than that from conventional hydroxypropyl methylcellulose (HPMC) based matrices, without any incorporated acidic additives.     

HPLC法测定氢溴酸右美沙芬分散片中氢溴酸右美沙芬的含量

目的:建立高效液相色谱法测定氢溴酸右美沙芬分散片中氢溴酸右美沙芬的含量.方法:采用高效液相色谱法,色谱柱为TIAMHE○R C 18(200 mm×4.6 mm,5μm);流动相为甲烷磺酸溶液-乙腈(70:30);检测波长:280 nm,柱温:30℃;流速:1.0 ml/min.结果:氢溴酸右美沙芬在49.5~346.5μg/ml的浓度范围内,其浓度与峰面积呈良好线性关系(r=0.9999).平均回收率为100.05%,RSD为0.87%.结论:高效液相色谱法简便,快捷,精密度高,可用于氢溴酸右美沙芬分散片中氢溴酸右美沙芬含量测定.     

氢溴酸右美沙芬口服液在正常人体内的生物利用度

氢溴酸右美沙芬剂量小,体内代谢迅速而广泛,母体药物浓度测定困难。本文通过测定氢溴酸右美沙芬的主要活性代谢物——去甲右美沙芬的血药浓度,进而对氢溴酸右美沙芬口服液在正常人体内的生物利用度进行研究。结果表明,8例正常人口服氢溴酸右美沙芬30mg 后,在体内可迅速转化为去甲右美沙芬,约在2h 达高峰浓度,T_(1/2)在1.7～4.7h。口服液的Tmax 较片剂明显提前,统计学t 检验有显著性差异(P<0.05);但Cmax 和AUC 在两种剂型间基本一致。     

Normal-phase LC method for simultaneous analysis of pseudophedrine hydrochloride,dextromethorphan hydrobromide,chlorpheniramine maleate,and paracetamol in tablet formulations

A simple, precise, and accurate method is developed and validated for the analysis of pseudophedrine hydrochloride, dextromethorphan hydrobromide, chlorpheniramine maleate, and paracetamol in tablet formulations. The method has shown adequate separation of the four ingredients from each other. Separation was achieved on a silica column (5 μm, 125 × 4.6 mm inner diameter) using a mobile phase consisting of methanol/ammonium dihydrogen phosphate buffer (90:10, v/v) at a flow rate of 1.0 ml/min and UV detection at 220 nm. This new method is validated in accordance with USP requirements for new methods for assay determination, which include accuracy, precision, selectivity, linearity and range, robustness and ruggedness. The current method demonstrates good linearity over the range of 0.15–0.45 mg/ml of pseudophedrine hydrochloride with r² of 0.996, and in the range of 0.075–0.225 mg/ml of dextromethorphan hydrobromide with r² of 0.992, and in the range of 0.01–0.03 mg/ml of chlorpheniramine maleate with r² of 0.994, and in the range of 0.25–0.75 mg/ml of paracetamol with r² of 0.991. The average recovery of the method is 99.7%, 98.6%, 98.1%, and 99.2% for pseudophedrine hydrochloride, dextromethorphan hydrobromide, chlorpheniramine maleate, and paracetamol, respectively. The degree of reproducibility of the results obtained as a result of small deliberate variations in the method parameters and by changing analytical operator has proven that the method is robust and rugged.     

黄藤素缓释片释放度的测定及其释药特性

目的　进行黄藤素缓释片释放度的测定及释药规律的研究。方法　采用紫外分光光度法测定黄藤素缓释片的释放度,并进行释药规律的研究。结果　测定波长为342nm ,黄藤素在3. 0～1 0 . 0 μg·ml-1 范围内线性关系良好(r =0 . 9999)。其体外释放特性符合Higuchi模式。结论　黄藤素缓释片释药机理是扩散和骨架溶蚀协同作用,而非单纯Fick扩散。     

Influence of hydrogel structure on the processes of water penetration and drug release from mixed hydroxypropylmethyl cellulose/thermally pregelatinized waxy maize starch hydrophilic matrices

The kinetics of water penetration and molsidomine release from both hydroxypropylmethyl cellulose (HPMC) and mixed HPMC/thermally pregelatinized waxy maize starch (SDWMT) hydrophilic matrices has been examined in 0.1 mol x dm(-3) HCl (pH 1.0) and 0.06 mol x dm(-3) Na3PO4/HCl buffer (pH 6.8). The rheological oscillatory test parameters of their gel layers obtained by swelling of the matrices in the two aqueous media have been observed. The kinetic swelling properties of mixed HPMC/SDWMT hydrogels (i.e. degree and velocity of both water penetration and swelling, transport mechanism which controls solvent sorption) directly influence the drug release behaviour and the structural features of the formed gel layer. Both diffusion processes are diffusion-controlled ones, their mechanisms being influenced insignificantly by the relaxation properties of the hydrated macromolecules. It has been established by means of comparative viscoelastic analysis, that mixed HPMC/SDWMT hydrogels demonstrate the typical behaviour of 'filled' composite systems having poor adhesion between the surface of the elastic SDWMT 'filler' and the continuous HPMC phase. Due to the inter-phase relations between the swollen starch granules and the linear cellulose derivative as well as to the specific structure of amylopectin molecule, the pregelatinized waxy maize starch shows a stronger influence on the velocities of both water penetration and drug release from mixed HPMC/SDWMT matrices.     

氢溴酸右美沙芬注射液含量测定及其降解物质检查

采用高效液相色谱法和紫外分光光度法测定氢溴酸右美沙芬注射液含量,并对高效液相色谱法和薄层色谱法检查注射液降解产物进行了比较。结果表明HPLC法既可准确测定注射液含量,又能准确检测出药物发生降解时药物定量变化。     

盐酸维拉帕米脉冲释放片体内外释药特性

目的：研究盐酸维拉帕米脉冲释放片体内外释药特性。方法：用干法压制包衣技术制备盐酸维拉帕米脉冲释放片，调整包衣中致孔剂用量，通过体外释放度试验考查时滞，并用HPLC法测定家兔血药浓度，考查体内外时滞的相关性。结果：体内外时滞基本相符。结论：可用体外时滞预测体内的时滞。     

复方美愈缓释片的高效液相色谱法分析

目的 :采用反相高效液相色谱法以程序变换控制记录积分衰减因子的方法 ,测定复方美愈缓释片中愈创木酚甘油醚和氢溴酸右美沙芬的含量。方法 :色谱柱为 Shimadzu VP-ODS(15 0 mm× 4.6mm) ,流动相为乙腈 -甲醇 -0 .0 1mol/ L 的三乙胺水溶液 (PH=3 .5 ) (18∶ 15∶ 67) ,检测波长 :2 76nm,流速为 1.0 ml/ m in。结果 :愈创木酚甘油醚和氢溴酸右美沙芬线性范围分别为 5 5 .9～ 782 .6μg/ ml和 4.2～ 5 8.8μg/ ml,平均回收率分别为 98.99% ,RSD1.2 % (n=7) ;10 2 .9% ,RSD 1.6% (n=7)。结论 :该方法可以用于美愈缓释片的含量测定     

4-氨基水杨酸钠结肠定位包衣片的制备与体外释放

目的:制备pH依赖和时间双重控制的4-氨基水杨酸钠结肠定位给药系统,并考察其体外释药行为。方法:以渗透型丙烯酸树脂EudragitRL与EudragitRS混和包衣液作为内层缓释层,pH依赖型丙烯酸树脂EudragitFS作为外层肠溶层,以柠檬酸三乙酯作为增塑剂,使用可调速糖衣机包衣,并研究包衣片在模拟人体胃肠道环境中的释放情况。结果:系统在0.1mol·L--1盐酸中2h无药物释放,在pH6.5的磷酸盐缓冲液中12h几乎无药物释放,在pH7.0和pH7.4时呈缓慢释放,且pH越高,释药时滞越短,肠溶层厚度的增加可延长释药时滞,12h内释药完全。结论:用渗透型丙烯酸树脂EudragitRL与EudragitRS的混合液作为缓释层,用pH依赖型丙烯酸树脂EudragitFS作为肠溶层可制备4-氨基水杨酸钠结肠定位包衣片。     

高效液相色谱法测定人血中氢溴酸右美沙芬浓度

目的研究氢溴酸右美沙芬在健康志愿者体内的血药浓度。方法采用高效液相色谱法测定8例健康受试者口服右美沙芬糖浆和片剂后不同时间血浆中的美沙芬浓度。结果右美沙芬在5--500 ng/ml浓度范围内呈良好线性关系（r=0.9965）。结论本法精密,准确,可用于氢溴酸右美沙芬的药动学研究。